The reinforcing properties of nicotine are thought to arise from the ability of the drug to stimulate the release of neurotransmitters from nerve endings of the brain. With prolonged exposure, nicotinic receptors become desensitized with a concomitant loss of functional activity. Long- term desensitization has been suggested as the mechanism responsible for the increase in brain nicotinic receptor density seen in animals administered nicotine and in human cigarette smokers. Interestingly, animals studies have indicated that nicotinic receptor upregulation occurs most effectively when stimulating concentrations of nicotine are achieved, even if only periodical, rather than by low-dose constant infusion. Since the steady-state brain levels of nicotine achieved with low-dose nicotine infusion are sufficient to maintain nicotinic receptors in a constant state of desensitization, this indicates that long-term desensitization may not fully account for receptor upregulation. Studies in our lab and others have indicated that high-level nicotine exposure can produce a long-lasting decreased in receptor function which has been termed receptor inactivation. It is possible that this inactivation process, rather than constant desensitization, is responsible for the increase in central nicotinic receptors seen with chronic nicotine administration. Also, several studies have shown that, although there is an increased number of receptors, there is a decrease in receptor-mediated functional activity, again indicating some form of receptor inactivation may occur. This proposal is designed to characterize the processes of receptor stimulation, desensitization, inactivation and upregulation produced by nicotine and several other potent nicotinic agents using a combination of in vitro superfusion, receptor binding, and in vivo drug administration studies. In addition, correlations between the potency and efficacy of these agents to produce the various activities may provide an indication of the functional consequences of these processes. The results of this study will expand our knowledge of the complex relationship between the concentration, duration and frequency of nicotinic drug exposure and the processes of receptor stimulation, desensitization, inactivation and upregulation. The importance of nicotine as a dependent drug, the current wide-spread use of transdermal nicotine, and the potential possibilities for nicotinic agonists as therapeutic agents in patients with cholinergic deficit all indicate that an understanding of these processes is important.